Accumulating evidence from many different types of scientific studies indicate that inadequate intake of the B vitamin, folate, increases the risk of several cancers. The evidence is most compelling for cancer of the colorectum. However, the prevailing evidence suggests that folate depletion only results in cancer when it operates in concert with other ill-defined genetic and environmental predispositions to cancer. The principle investigator of this K05 application has devoted the majority of his career to investigating this relationship between folate and carcinogenesis. He is now poised to begin to investigate how several other factors, such as age, tobacco, and vitamin B6 and B12 depletion interact with folate metabolism in such a way as to accentuate the promotion of cancer conveyed by folate depletion alone. The financial resources afforded by this K05 award will enable the investigator to dispense with a very substantial burden of clinical and administrative duties in his medical center, thereby allowing him to devote nearly all of his professional energies towards the elucidation of the factors outlined above. The investigator also has an excellent track record of mentoring and has trained several young people who are now fully independent scientists themselves. This award, therefore, would free up enough of the Principal Investigator's time to enable him to take on additional trainees in the future. The studies that are intended to address the abovementioned issues include human and animal experiments that are complimentary in nature. Well-established rat models of B-vitamin depletion, aging, and colorectal carcinogenesis will be used to define which combinations of B-vitamin deficiencies and elder age can potentiate the procarcinogenic milieu produced by folate depletion, and by what mechanisms these effects are mediated. The identification of novel, previously unsuspected, pathways towards cancer will be elucidated by use of DNA microarray technology. A human study, designed to examine habitual cigarette smokers, will examine how smoking alters the metabolism of these vitamins in the mouth in order to convey an increased risk of oral cancer, and whether surrogate biomarkers of this cancer can be improved by the use of folate supplementation.